Nuclear erythroid related factor-2 (Nrf2), a redox-transcription factor, plays a critical role in the detoxification of electrophilic and reactive oxygen species that halt various biochemical and molecular processes. This makes it a candidate for regulation by polyphenols. This study investigates the capability of chalcone dimers (lophirones B and C) to induce expressions and activities of cytoprotective enzymes. Chalcone dimers administration to rats not only induced the Nrf2, but also suppressed cytoplasmic Kelch-like ECH-associated protein 1 (Keap1) expressions. In addition, the chalcone dimers significantly (p < 0.05) increased the expressions and activities of nicotinamide adenine dinucleotide and reduced quinone oxidoreductase-1, glutathione-S-transferase, epoxide hydrolase and uridyl glucuronosyl transferase in rat liver. Also, activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in rat liver increased significantly (p < 0.05). Overall, lophirones B and C increased the expressions and activities of cytoprotective proteins in rat liver possibly through the reduction of cytoplasmic Keap1 expression, leading to the nuclear translocation of Nrf2.